Current and Emerging Approaches in Antileishmanial Research
Denis MartinDrugs for Neglected Diseases initiative
WorldLeish4, February 3rd, 2009
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cted Current Treatments
Drugs PentavalentAntimonials
Amphotericin B LiposomalAmphotericin B
Miltefosine Paromomycinsulphate
Regimen 20 mg/kg daily for 20-30days(depends on geographicarea)
1 mg/kg e.o.d.for up to 30 Days(15mg/Kg total dose)
5-20 mg/kgtotal dose in 4-10 dosesover 10-20 days
1.5-2.5 mg dailyover 28 days(India only)
15mg/kg/ for21 days(India only)
Marketing authorisationholder
Albert David (SSG)GSK (Pentostam)Sanofi Aventis (Glucantime)
Bristol Meyers Squibb(Fungizone)Generic companies
Gilead (AmBisome®) Paladin (Impavido) Gland Pharma/ IOWH
Administration iv or im iv Iv Oral im
Clinical efficacyAsiaAfricaSouth America
35-95% (dependingon geographic area)
> 97% all regions > 97%; single dose: 91%Not fully establishedNot fully established
94-97% (India);Not establishedNot established
94% (India)In evaluationAssumed to be limited
Resistance As high as 60%(Bihar, India)
Not documented Not documented Lab isolates Lab isolates
Toxicity +++Cardiac toxicity,pancreatitis,nephrotoxicityhepatotoxicity
+++Nephrotoxicity(in patient care needed)
+Some nephrotoxicity
+Gastro-intestinal(20-55% of patients, usually mild),nephrotoxicityhepatotoxicityPossible teratogenicity
+Nephrotoxicityototoxicityhepatotoxicity(all relatively rare)
Approximatecost of drugsper course*USD (Euros)
SSG (AD) ~$50 (37€)Glucantime (SA)~ $70 (52 €)(Based on 30 day course)
Generic price:~ $117 (87€)
Preferential price: $280(207€)(for 20mg/kg total dose)Commercial price:~10x above costs
Preferential price: ~ $74 ( 54 €)(can be obtained at 46€ if buying>75 000 packs)Commercial price: ~ $150
~ $10 (7.3 €)
Issues Quality controlAvailabilityLength of treatmentPainful injectionToxicityResistance in India
Need for slow iv infusionDose-limitingnephrotoxicityHeat stability
PriceNeed for slow ivinfusionHeat stability(Stored <25° C)
PricePossible teratogenicityPotential for resistancePatient compliance
Efficacy variable Between and within regions
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Issues with Current Treatments•• SSG/ SSG/ antimonialsantimonials:: SAFETY, RESISTANCE, DURATIONAfrica: registered in Sudan, Ethiopia, Kenya. Used for all above indications!India: SSG failure in Bihar, still effective other areas
•• AmBisomeAmBisome®®:: COST, FEASIBILITYAfrica: MSF Ethiopia field use, Dose escalation study plannedIndia: Phase 2 data+, combo studies done/ planned, MSF- 20mg in field setting (1000+)
•• AmphoAmpho B:B: SAFETY, DURATION, COSTAfrica: being replaced by Ambisome, limited useIndia: Large scale use especially in private sector in Bihar (SSG failure)
•• ParomomycinParomomycin:: DURATION, EFFICACY?Africa: currently under trial, used as part 1o Rx in S Sudan by MSF India: Registered for use, Phase 4 ongoing
•• MiltefosineMiltefosine:: DURATION, SAFETY, COMPLIANCEAfrica: RCT done Ethiopia, no current trials underway, 2 previously planned (no funding)India: Registered in India, WHO roll out, In private sector, In combo studies planned
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VL Target Product ProfileTarget
Target Label VL and PKDLSpp All speciesDistribution All areasTarget Population Immunocompetent and
immunosuppressedClinical Efficacy > 95%Resistance Active against resistant strainsSafety and Tolerability No AEs requiring monitoringContraindications NoneInteractions None- Compatible for combination
therapyFormulation Oral / im depotStability 3 yrs in zone 4Treatment Regimen 1/day for 10 d po/ 3 shots over 10 d
Cost < $10 / course ($20 in 7 years)
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PreclinicalEfficacy & Safety
RegistrationClinical Ph IV
•
DNDi projects
•
Non-DNDi projects
VL Combo Asia
Buparvaquone
Oral AmphoB
(BDSI)
PM-SSG Africa
PM – India(iOWH)
Amphomul(Bahrat)
MiltefosineAfrica
AmBisome®Africa
Combination TrialsSitamaquine
& Tafenoquine
(GSK)
Oral AmphoB(iCo)
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DNDi Near- and Long-Term Strategy
• Ensure appropriate use of existing treatments through clinical validation of combination therapy treatments.
• Develop new formulations of existing drugs (ie. Amphotericin B)
• Identify and develop NCE
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DNDi R&D Portfolio - 2009
Lead ID
PreclinicalEfficacySafety
Lead Optimization
Ph I Ph IV &Access
Registra- tionPh II Ph IIIScreen
30% 65% 55% 70% 50% 65%55% 95%
• Consolidation with strategic focus
– By chemical structure
– By target– General
screening– New partners
• Reference Screening Centers
– LSHTM– STI– U. Antwerp
HATScynexis
VLAdvinus,
CDRI
ChagasCDCO/
Epichem
New HAT Candidate
Buparva-quone
AmphoB polymer
Oral AmphoB
Fexinidazole (HAT)
VL CombinationIn Asia
Paromomycin in E. Africa
AmBisome® in E. Africa
Miltefosine in E. Africa
VL Combination in LA
Paediatric Benznidazole
Azoles (Chagas)
FACT-ASAQ
FACT-ASMQ
NECT
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DNDi Early-Stage Discovery • Forge alliance with group with complementary skill set
– Multiple targets, broad capabilities, proven record, less management burden (U. Dundee)
• Continue to be opportunistic– Phasing out some one-off type of agreements as they mature,consider
opportunities as the arise
• Data mining – STI, WRAIR
• Fill in gaps in HTS assays– Improvements in through-put for T. cruzi and Leishmania screens (IPK)
• Library access– Expand current list - pharma, ad hoc suppliers, – Sharing with PDPs– Targeted drug classes
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VL Lead Optimization Strategy
Screening Hit Expansion Lead Optimization
Reiterative cycles of medicinal chemistry
Parallel assessmentof DMPK Tox and
Potency
Pharmaceutical chemistry
GLP Toxicology
Lead to Candidate
DrugCandidate
CDRI - Advinus
Anacor
IRD
DNDi consortium is partially funded by the Bill & Melinda Gates Foundation.
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Buparvaquone
O O
O
O
H3C
OH
OH
O
HO
HOOH
OH OH
OH
OH OH
OCH3
CH3
CH3
CH3
N H2
Amphotericin B (AmB)
Amphotericin B
Oxaboroles
OBO
H
O
IC50 0.95 uM
OBO
N O
IC50 2.03 uM OBO
O
N IC50 2.69 uM
OBO
O
IC50 2.03 uM
2-substituted quinolines
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Different from Carbon
Trigonal Planar Tetrahedral
Boron is normally trivalent and trigonal planar in structureIt has an empty P-orbital & can form a new bond under specific conditionsThe new bond forms a tetrahedral structureExploiting the P-orbital reactivity allows rational drug design and creation of compounds with unique properties beyond traditional small molecule drugs
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Amphotericin B Formulations
• AmB is the most efficient treatment
• Cost, stability and route of administration are barriers for wider use
• Ongoing work to develop cheaper and orally active formulations
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O ONO O
Active estermonomer
CH2
CH3
COO
NO
O3
n
Active esterpolymer precursor
Controlled radical polymerisation
ATRPO Cl
Acid chloride
OHNO O
+
NHS
12
DCM, Et3N
AmBNaOH
CH2
CH3
COO-
n
4
AmB-PMA Complex
Non-covalent complex
Polymerisation Reaction
Synthesis of monomer Preparation of AmB complex
Potential cheaper iv Ampho B formulation
O O
O
O
H3C
OH
OH
O
HO
HOOH
OH OH
OH
OH OH
OCH3
CH3
CH3
CH3
N H2
Amphotericin B (AmB)
Replace the liposoamal part by polyacylic acid polymer
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• Complexes have been made with the following features:– MW: from 12 kDa to 150 kDa– Loading: from 15% to 60%– Amphotericin dose: from 0.75 to 1.5 mg
• Complexes can be made directly from the polymer. No need to use the precursor polymer.
• No sign of AmB-related toxicity in mice.
• Issues:How the physicochemical properties of the complex correlates to efficacy in the in vivo model.
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AmB Oral Formulations
• Orally active AmB formulations under development
– Lipid-based formulation developed by iCo pharmaceuticals (pre-clinical stage)
– "Cochleates" formulation developed by BDSI in collaboration with DNDi
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BDSI Cochleates Technology
•Stable, phospholipid-calcium precipitates
•Self-assembling crystalline units
•Multilayered structure, containing little or nointernal aqueous space
•Resistant to degradation in GI tract
•Increases processing and shelf-life stability
•Composed of naturally occurring materials
•Very inexpensive cost of goods andmanufacturing
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iCo Lipid-Based Formulation
• The laboratory of Dr. Kishor Wasan of the University of British Columbia has made significant strides toward the development of a proprietary, lipid- based AmB formulation for oral administration.
• Further development licensed to iCo Therapeutics and collaboration with CPDD.
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Conclusions
• No new treatments recently made available to treat leishmaniasis
• Limited number of promising chemical series available
• International consortium built around Indian partners with international collaborations
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Teams
Advinus Team (Management)Koushik Das SharmaVadiraj GopinathVikram RamanathanSanjiban Banerjee
CDRI TeamDr. S.K.PuriDr. Suman GuptaMs NishiMrs Shraddha Sane
Advinus Team (Scientists)Vinayak AdimuleManjunath MogerKailasam RDhayanithi VSabath Kumar PVenkatesan Jayakumar SSrinivas Rao PSaswati RoyShubhangi BhosaleSuresh PPaniraj A.S.